Dietary phosphorus regulates serum fibroblast growth factor-23 concentrations in healthy men

CONTEXT: Fibroblast growth factor 23 (FGF-23) is important in the regulation of phosphorus and vitamin D metabolism. States of excess circulating FGF-23 are associated with renal phosphate wasting and inappropriately low serum 1,25-dihydroxyvitamin D [1,25(OH)(2)D] concentrations. Conversely, states of absent or biologically inactive circulating FGF-23 are associated with increased serum phosphorus and 1,25(OH)(2)D concentrations. Restriction of the dietary intake of phosphorus increases renal phosphate reabsorption and 1,25(OH)(2)D production, whereas the opposite occurs when dietary phosphorus is supplemented. OBJECTIVE: We sought to determine whether serum FGF-23 concentration is regulated by dietary phosphorus and thereby mediates the physiological response of serum 1,25(OH)(2)D to changes in dietary phosphorus. DESIGN, SETTING, AND PARTICIPANTS: We studied 13 healthy men as inpatients during a 4-wk dietary phosphorus intervention study. INTERVENTION: Subjects consumed a constant diet that provided 500 mg of phosphorus per day, which was supplemented to achieve three phosphorus intakes, each of 9 d: 1) control = 1500 mg/d; 2) supplemented = 2300 mg/d; 3) restricted = 625 mg/d. Intakes of calcium, sodium, potassium, magnesium, and energy were constant. MAIN OUTCOME MEASURE: Serum FGF-23, 1,25(OH)(2)D, phosphorus, and calcium concentrations were measured. RESULTS: Serum FGF-23 concentrations decreased significantly from 30.7 +/- 8.7 pg/ml during phosphorus supplementation to 19.6 +/- 7.0 pg/ml during phosphorus restriction. Serum 1,25(OH)(2)D concentrations increased significantly from 29 +/- 10 pg/ml (75 +/- 26 pmol/liter) during phosphorus supplementation to 40 +/- 16 pg/ml (104 +/- 42 pmol/liter) during phosphorus restriction (P < 0.001). Serum 1,25(OH)(2)D concentrations varied inversely with those of serum FGF-23 (r = -0.67, P < 0.001). CONCLUSIONS: We conclude that in healthy men, changes in dietary phosphorus within the physiological range of intakes regulate serum FGF-23 concentrations and suggest that dietary phosphorus regulation of 1,25(OH)(2)D production is mediated, at least in part, by changes in circulating FGF-23.     

Do size,histology, or cytology of colorectal adenomas and their removal influence serum CEA?

Based on the adenoma-carcinoma sequence the authors studied whether determination of serum carcinoembryonic antigen (CEA) provided any conclusions concerning malignant transformation of a colorectal adenoma. In 32 patients with single or multiple adenomas, serum CEA did not differ from 119 healthy individuals. In 43 percent, a decrease of CEA could be observed after polypectomy, while it increased in 22 percent or remained unchanged in 35 percent. No correlation was found between adenoma volume and serum CEA. There was a tendency toward a higher serum CEA level in patients with villous adenoma as compared with those with tubular structure. CEA concentrations were independent from the degree of cellular atypia, but polypectomy was followed by a decrease of serum CEA in villous adenoma or of moderate cellular atypia, reflecting a possible influence on production or shedding of CEA by these subtypes of adenoma. The results indicate, therefore, that serum CEA is not able to recognize the malignant potential of colorectal adenoma.     

Effect of clonidine on serum inorganic phosphorus in patients with essential arterial hypertension

The decrease in arterial blood pressure in patients with essential arterial hypertension treated with clonidine is associated, in 88.9% of cases, with a rise in serum inorganic phosphorus. The increase of inorganic phosphorus in the serum of patients with hypophosphataemia, during clonidine therapy, is higher (P less than 0.001) than in hypertensive patients with normal values of serum phosphorus (P less than 0.01). This effect is more significant in overweight hypertensive patients (P less than 0.0005) than in normal weight hypertensives (P less than 0.02). No correlation was noted between the rise of serum inorganic phosphorus and the decrease in systolic and diastolic arterial blood pressure. The rise of serum phosphorus concentration in hypertensive patients is attributed to inhibition of insulin release and enhancement of growth-hormone secretion induced by clonidine.     

Electrolyte and acid-base disturbances in the management of leukemia.

Electrolyte disturbances in leukemia can be the result of the disease process or drug therapy. One group of electrolyte abnormalities is related to the stage of the leukemic process. Included in this group are newly diagnosed patients who may show elevated serum potassium, phosphorus, and magnesium--a result of their release from malignant cells after cytotoxic therapy or their accumulation due to urate nephropathy. Patients in remission usually have normal serum electrolyte concentrations, but acute leukemia patients during relapse may have hypokalemia, hypophosphatemia, and hypomagnesemia. This imbalance may be related to cellular uptake of these electrolytes in the presence of inadequate dietary intake. Other factors contributing to electrolyte derangements, and related to the leukemic process, include hyponatremia and hypochloremia secondary to the SIADH, hypokalemia in acute monocytic or acute myelomonocytic leukemia due to lysozyme-induced tubular damage, hypercalcemia possibly secondary to leukemic infiltration of bone or parathyroid glands (with PTH release), or production of a PTH-like substance by leukemic cells. Nonspecific factors related to the disease process which may aggravate the electrolyte imbalance include gastrointestinal loss through nausea, vomiting, and malnutrition. The drug-related electrolyte abnormalities include cyclophosphamide- and vincristine-induced SIADH; decreased serum sodium, chloride, potassium, and calcium concentrations as a result of polymyxin B nephrotoxicity; hypokalemia and hypomagnesemia secondary to amphotericin B; hypocalcemia, hypophosphatemia, and hyperphosphaturia due to L-asparaginase-induced hypoparathyroidism; hypokalemia due to a nonreabsorbable anion effect of antibiotics in the distal tubule or changes in membrane ionic transport of all cells by large doses of antibiotics. Electrolyte disturbance in leukemia thus have a multifactorial pathogenesis which can best be delineated according to the stage of the leukemic process and the drugs being used. Recognition of the cause or causes in a particular patient is essential for an effective approach to management. This review emphasizes the need for routine measurement of serum electrolytes during all phases of the leukemic process.     

In Vitro Detection of Cytotoxic Cellular Immunity Against Tumor-Specific Antigens by a Radioisotopic Technique

[(3)H]Thymidine-labeled tumor cells are used to evaluate the cytotoxic cellular immune response against tumor-specific antigens; the loss of label due to destruction and detachment of target cells from the surface of the culture vessel is measured. Spleen cells from mice immunized against Moloney virus-induced rhabdomyosarcoma specifically destroyed the sarcoma cells, while cells from normal syngeneic mice did not. Peripheral blood lymphocytes from patients with malignant tumors were specifically cytotoxic to autologous tumor cells and to allogeneic tumor cells histopathologically identical to the autologous tumor, but not to autologous nonmalignant fibroblasts, or to allogeneic tumor cells from a histologically dissimilar tumor. Serum from the same patients specifically protected autologous tumor cells from lymphocyte cytotoxicity. This serum-mediated protection of tumor cells against autologous cellular immunocytotoxicity also extended to histologically identical allogeneic tumor cells. Cross-reactivity of anti-tumor cellular immunocytotoxicity in vitro, and its "blocking" by autologous serum, strongly suggest the presence of common tumor antigens. The antagonism demonstrated in vitro between serum and cellular immunity may explain the continued growth of malignant tumors in the face of demonstrable cellular immunity.     

1,25-Dihydroxycholecalciferol effect on serum phosphorus homeostasis in rats.

It has recently been shown that 1,25-dihydroxycholecalciferol (1,25-(OH)2D3) increases the serum phosphorus concentration of rats on a low-phosphorus diet. While studying the biological activity of 1,25(OH)2D3, we observed that under certain circumstances 1,25-(OH)2D3 would decrease the serum phosphorus concentration. The analysis of all data obtained in rat experiments during the past 3 years revealed highly significant linear correlations (P less than 0.001) between changes of serum phosphorus concentrations after the administration of 1,25-(OH)2-D3 (130 pmol/d for 1 or 5 days) and serum phosphorus or calcium levels in the animals before injection. Similar correlations could only be found with the higher dose of 25-hydroxycholecalciferol (130 pmol/d for 5 days). Another vitamin D3 metabolite, 24,25-dihydroxycholecalciferol, had no effect on serum phosphorus concentrations under our experimental conditions. The 1,25-(OH)2D3 effect on serum phosphorus concentration does not require the presence of circulating parathormone and/or calcitonin. We suggest that 1,25-(OH)2D3 might be an important factor in serum phosphorus homeostasis.     

Effects of induced total-body hyperthermia on phosphorus metabolism in humans

The effects of total-body hyperthermia on phosphorus homeostasis are controversial. To evaluate the problem, 10 clearance studies were performed in seven patients undergoing total-body hyperthermia as an adjunct to the treatment of solid malignant tumors. Total-body hyperthermia was associated with significant reduction in plasma phosphorus concentration from a baseline value of 3.51 +/- 0.18 to 0.6 +/- 0.1 mg/dl (p less than 0.001), returning to baseline following cessation of total-body hyperthermia. The clearance of phosphorus increased from 15.2 +/- 2.5 to 26.1 +/- 3.1 ml per minute (p less than 0.01), and the fractional excretion of phosphorus increased from 11.37 +/- 2.2 to 47.68 +/- 9.7 percent (p less than 0.01). The reduction in plasma phosphorus during total-body hyperthermia was also associated with a significant reduction in the renal threshold phosphorus concentration from 3.17 +/- 0.16 to 0.38 +/- 0.08 (p less than 0.001). The changes in phosphorus homeostasis during total-body hyperthermia were independent of changes in circulating parathyroid hormone level, urinary cyclic AMP excretion, and arterial carbon dioxide tension.     

Treatment of severe hypophosphatemia.

Aspects of phosphate biochemistry pertinent to therapy, the distribution of phosphorus in body compartments, therapeutic phosphorus preparations, prevention of hypophosphatemia, therapeutic guidelines, and side-effects of phosphorus therapy are reviewed. Severe hypophosphatemia (less than 0.32 mmol/litre or less than 1 mg/dl) can occur with normal or depleted body stores. Because a large amount of phosphorus may shift rapidly between the extracellular and intracellular or bone compartments, the size of a possible total body deficit cannot be estimated from the serum phosphorus level. Similar shifts may occur unpredictably during repair of hypophosphatemia. Therefore, correction of hypophosphatemia in any patient must be empiric and the response of serum levels to therapy should be followed closely. We discuss a method likely to correct hypophosphatemia while minimizing side-effects.     

Skeletal turnover and total body elemental composition during extended calcitonin treatment of Paget's disease

Twenty patients with generalized symptomatic Paget's disease had serial measurements of radiocalcium turnover and/or total body elemental composition by in vivo neutron activation analysis during long-term calcitonin therapy. Despite maintained clinical improvement, seven of 15 patients showed partial or total loss of the initial decelerating effect of calcitonin on skeletal turnover, whereas the remaining eight patients maintained the calcitonin-induced deceleration. The changes in skeletal turnover were roughly proportional to the induced changes in serum alkaline phosphatase and urinary hydroxyproline. However, disparities in the magnitude of the changes among the three parameters were not uncommon. Total body calcium was increased by a mean of 22% above predicted prior to calcitonin and decreased significantly by 4% during long-term calcitonin treatment. Total body phosphorus, nitrogen, and sodium also decreased. The phosphorus and sodium losses appeared to be mostly from the skeleton. These data confirm histologic evidence of the disappearance of pagetic bone, resumption of normal lamellar bone formation, and radiographic evidence of a decrease in bone volume during calcitonin treatment and indicate the relative magnitude of this effect. The action of calcitonin in this regard possibly represents a specific effect on Paget's disease beyond its general skeletal effect to reduce cellular activity.     

Effect of calcitonin on salivary phosphorus and calcium excretion in sheep

Three thyroidectomized sheep were infused intravenously with porcine calcitonin at a rate of 30 mi.u./h per kg and three sham-operated sheep were infused with vehicle for 5 h. Saliva was collected from the left parotid duct by cannulation for 10 min in every hour. Salivary secretion rates were not changed in either thyroidectomized or sham-operated sheep throughout the experiment. Before the infusion, salivary phosphorus excretion was less in thyroidectomized sheep than in sham-operated animals. Calcitonin infusion increased salivary phosphorus excretion and decreased serum phosphorus concentrations in thyroidectomized sheep. Vehicle infusion did not affect salivary phosphorus excretion in sham-operated sheep. Serum concentrations and salivary excretion of calcium were decreased by calcitonin infusion into thyroidectomized sheep but were not changed in sham-operated sheep infused with vehicle. Calcitonin infusion increased serum parathyroid hormone concentrations in thyroidectomized sheep after the decrease of serum calcium concentrations. However, vehicle infusion did not affect serum parathyroid hormone concentrations in sham-operated sheep. There was little change of cyclic AMP excretion during the experiment in either thyroidectomized or sham-operated sheep. It is concluded that calcitonin increases salivary phosphorus excretion in sheep.     

Dietary egg whites for phosphorus control in maintenance haemodialysis patients: a pilot study

Background : High dietary protein intake is associated with greater survival in maintenance haemodialysis (MHD) patients. High‐protein foods may increase dietary phosphorus burden, which is associated with increased mortality in these patients. Hypothesis is: an egg white based diet with low phosphorus to protein ratio (<1.4 mg/g) will lower serum phosphorus without deteriorating the nutritional status in MHD patients. Objective : We assessed serum phosphorus and albumin levels in MHD patients who agreed to ingest one meal per day with pasteurised liquid egg whites without phosphorus additives, as principal protein source. Methods : Thirteen otherwise stable MHD patients with serum phosphorus >4.0 mg/dl agreed to consume eight ounces (225 g) of pasteurised liquid egg whites one meal per day for six weeks. Recipes were suggested to improve diet variety. Results : Thirteen participating patients included seven women, three African Americans and five diabetics. Twelve patients exhibited drop in serum phosphorus. Mean population fall in serum phosphorus was 0.94 mg/dl, i.e. from 5.58 ± 1.34 (mean ± SD) to 4.63 ± 1.18 (p = 0.003). Serum albumin showed an increase by 0.19 g/dl, i.e. from 4.02 ± 0.29 to 4.21 ± 0.36 g/dl (p = 0.014). Changes in phosphorus pill count were not statistically significant (p = 0.88). The egg white diet was well tolerated, and recipe variety appreciated. Conclusion : Pasteurised liquid egg whites may be an effective diet component lowering serum phosphorus without risking malnutrition. Controlled trials are indicated to examine egg white based dietary interventions in MHD patients at home or during haemodialysis treatment.     

Evidence for mild reversible hyperparathyroidism in distal renal tubular acidosis.

Circulating levels of immunoreactive parathyroid hormone were measured in six patients with distal renal tubular acidosis before and during two years of long-term alkali therapy. Parathyroid hormone level was elevated modestly in five patients before treatment and fell, gradually during treatment to normal or near normal levels. Urine calcium level fell, serum calcium level rose, and renal phosphorus reabsorption rose during treatment. Stopping treatment briefly caused reversion of serum parathyroid hormone and calcium levels and renal phosphorus reabsorption to pretreatment values within eight weeks. Mild hyperparathyroidism is present in renal tubular acidosis and reverses with alkali treatment.     

Elevated secretion and action of serum parathyroid hormone in young adults consuming high phosphorus, low calcium diets assembled from common foods

We sought to determine if the high phosphorus, moderately low calcium intake typical of U.S. teenagers and young adults alters parathyroid function as it does in experimental animals. Because those animals ultimately developed osteopenia, it has been suggested that low dietary calcium to phosphorus ratios may reduce peak bone mass and increase susceptibility to osteoporotic fracture later in life. However, it is not known whether PTH secretion or action increases in response to commonly consumed phosphorus-rich, calcium-poor foods. We studied the 24-h mineral and hormonal responses of eight men and eight women, aged 18-25 yr, after 8 days of ingesting a control diet that had calcium (820 mg) and phosphorus (930 mg) contents near the recommended daily intakes, and a test diet with calcium and phosphorus contents (1660 mg phosphorus, 420 mg calcium) typical of current intakes. Both diets were made from common grocery store foods. The 24-h mean serum immunoreactive PTH levels increased in men (11%; P less than 0.006) and women (22%; P less than 0.003) during the test diet. In both sexes, the test diet significantly increased serum phosphorus, plasma 1,25-dihydroxyvitamin D, and urinary hydroxyproline and cAMP excretion; in women only it decreased serum ionized and total calcium levels. Thus, short term ingestion of a diet typifying current levels of calcium and phosphorus intake resulted in elevated serum iPTH levels and indexes of PTH action in young adults.     

Diagnostic significance of the determination of serum alpha-L-fucosidase in primary hepatocellular carcinoma

The results of determination of serum alpha-L-fucosidase (AFU) in healthy individuals, in patients with various liver diseases and non-liver malignant diseases were reported. In primary hepatic carcinoma the level of serum AFU was significantly higher than that in various other diseases and healthy persons (P less than 0.001). The serum AFU level was independent of AFP level (x = 1.24, P greater than 0.25). These data suggest that AFU may be a useful marker for the diagnosis of primary hepato cellular carcinoam with negative AFP.     

Solid tumors complicating Hodgkin's disease. A report on two patients with immunoglobulin deficiency.

Multiple epithelial malignant neoplasms developed in two patients with Hodgkin's disease subsequent to radiotherapy and intensive chemotherapy. At the time of diagnosis, each patient also demonstrated a serum immunoglobulin deficiency. The significance of the occurrence of solid tumors in patients following therapy for Hodgkin's disease and the significance of cellular and humoral immunodeficiency in Hodgkin's disease in relation to second cancer development were studied. We suggest the establishment of a registry of leukemias and solid tumors developing in patients treated for Hodgkin's disease and other malignant neoplasms, possibly with detailed recording of immunocompetence data.     

肝硬化患者糖负荷时的血磷变化

探讨肝硬化患者糖负荷时血磷变化,检测38例肝硬化患者口服葡萄糖耐量试验时的血磷变化。结果显示空腹血磷降低者2例（5．26％）,服糖后13例（34．21％）出现低血磷。肝硬化患者服糖后血磷呈直线降低,3小时达最低值。提示肝硬化患者服糖后易出现低血磷症,应注意加强血磷的检测。     

5-Azacytidine and renal tubular dysfunction

During initial trials of 5-azacytidine in adults with advanced acute leukemia, we unexpectedly observed acid-base, fluid, and electrolyte abnormalities that contributed directly to the deaths of two early patients. To evaluate this toxicity further, we studied 22 patients who received a total of 33 courses of combination chemotherapy that included 5-azacytidine. During 29 courses (88%) of treatment, polyuria, glucosuria, and/or transient changes in the serum concentrations of bicarbonate or phosphorus were detected. Spontaneous polyuria with demonstrable salt wasting and orthostatic hypotension occurred during seven courses (21%) of treatment. Inappropriate glucosuria was observed in nine courses (27%). In 24 courses (73%) the serum bicarbonate fell below the normal range. The urine became alkaline during 12 of these instances; the anion gap was not increased during the acidosis. Hypophosphatemia with serum phosphorus concentrations as low as 0.3 mg/dl occurred in 21 of 32 evaluable courses (66%). In the three patients studied the tubular reabsorption of phosphorus was 10%-18%. The renal abnormalities that were observed suggest both proximal and distal tubular damage from 5-azacytidine. Patients receiving 5- azacytidine should be monitored closely for manifestations of renal toxicity.     

Selective monocellular necrosis of Hodgkin's/Reed-Sternberg cells and their immunoreactivity to human serum antinuclear antibodies in NS- and MC-types of malignant lymphogranuloma.

The selective (apoptotic) necrosis of Hodgkin's cells in malignant lymphogranuloma appears to be etiologically quite different from focal one due to ischemic-vascular causes. The morphology and supposed etiopathogenesis of this cellular lesion, as well as the karyoclastic process-presumably apoptotic in nature-are briefly described and considered as a mechanism leading to cellular regression with subsequent destructuralization and release of DNA-reactive nucleoprotein material in form of free hematoxylin bodies. An original observation of the immunoreactivity of Hodgkin's cells with antinuclear antibodies of human serum in a case of collagenosis is also described.     

Dynamics of calcium metabolism and calcium-regulating hormones in pregnancy-induced hypertension

Serum concentrations of total calcium, ionized calcium and inorganic phosphorus in severe PIH were significantly lower than those in normal pregnancy during the 3rd trimester of pregnancy and continued to be low even at puerperium. On the other hand, serum concentrations of parathyroid hormone in severe PIH were significantly higher during the 3rd trimester of pregnancy and decreased at puerperium. Any remarkable differences in serum calcitonin levels were not found between severe PIH and normal pregnancy through the last trimester of pregnancy and puerperium. Serum concentrations of 1 alpha, 25-(OH)2 vitamin D3 increased significantly in the 3rd trimester of normal pregnancy, but in severe PIH, their increase was not observed, remaining at the normal levels of non-pregnant women. The kidney functions in the both groups were within the normal limits of non-pregnant women, but placental dysfunction was observed in severe PIH. These results suggest that the decrease in serum calcium and phosphorus levels might have occurred as a result of the decrease in the absorption of calcium and phosphorus from the intestine due to the decrease in serum 1 alpha, 25-(OH)2 vitamin D3 levels and that low serum 1 alpha, 25-(OH)2 vitamin D3 concentrations might be caused by the disturbance of the synthesis in the placenta rather than in the kidney.     

Role of 1,25-Dihydroxyvitamin D3 in Maintaining Serum Phosphorus and Curing Rickets

The intravenous injection of a single dose of 650 pmoles of 1,25-dihydroxyvitamin D(3) to rats fed a vitamin D-deficient, low-phosphorus diet caused an elevation of serum phosphorus within 5 hours which reached a maximum in about 10-12 hours. This elevated serum phosphorus returned to deficiency levels 2-3 days later. On the other hand, a single injection of 650 pmoles of 25-hydroxyvitamin D(3) produced a significant rise at 12 hours, reached a maximum in 24-36 hours, and was maintained for at least 7 days. The single dose of 1,25-dihydroxyvitamin D(3) supported little calcification of bone, whereas the 25-hydroxyvitamin D(3) produced marked calcification. Six-hundred and fifty pmoles of 24,25-dihydroxyvitamin D(3) increased serum phosphorus only slightly and induced no calcification. When 1,25-dihydroxyvitamin D(3) was given each day, a sustained increase in serum phosphorus and marked bone calcification resulted. In contrast to the serum phosphorus responses, intestinal calcium transport remained high 5 days after administration of a single dose of 1,25-dihydroxyvitamin D(3). Serum calcium was not changed appreciably by any of the metabolites.Thyroparathyroidectomized rats or rats fed a diet extremely deficient in phosphate still exhibited a marked elevation of serum phosphorus in response to 1,25-dihydroxyvitamin D(3). The effect of 1,25-dihydroxyvitamin D(3) on serum phosphorus was greatly reduced in nephrectomized rats, suggesting that the serum phosphorus response to 1,25-dihydroxyvitamin D(3) may arise from an enhancement of phosphate reabsorption in the renal tubules.It is suggested that 1,25-dihydroxyvitamin D(3) cures rickets in rats by increasing the concentration of serum phosphorus rather than by increasing serum calcium concentration and calcium absorption.